INSULIN

Insulin, a hormone produced by the pancreas, acts to maintain blood glucose levels within normal limits (60–120 mg/dL). This is accomplished by the release of small amounts of insulin into the bloodstream throughout the day in response to changes in blood glucose levels. Insulin is essential for the utilization of glucose in cellular metabolism and for the proper metabolism of protein and fat. Insulin Products
1. Purified Animal Insulins (porcine, bovine)-

purified by gel flitration, single peak Extremely low-risk of insulin allergy human insulins altering their

purity,

few contaminants

2. Recombinant human insulins (Humulin)-

3. Designer Insulins” – biochemical modifications of

absorption profile, duration of action

Drugs That Increase

the Hypoglycemic Effect of Insulin

Alcohol, angiotensin-converting enzyme (ACE) inhibitors, antidiabetic drugs, beta blocking drugs, calcium, clonidine, disopyramide, , monoamine oxidase inhibitors (MAOIs), salicylates, sulfonamides, tetracycline DISPLAY 49-2 Drugs That Decrease the Hypoglycemic Effect of Insulin antivirals, albuterol, contraceptives, oral corticosteroids, diltiazem, diuretics, dobutamine, epinephrine,_ estrogens, lithium, morphine sulfate, niacin, phenothiazines, thyroid hormones

DISPLAY 49-1 _ Select

DIABETES MELLITUS is a complicated, chronic disorder characterized by either insufficient insulin production by the beta cells of the pancreas or by cellular resistance to insulin. Insulin insufficiency results in elevated blood glucose levels, or hyperglycemia. As a result of the disease, individuals with diabetes are at greater risk for a number of disorders, including myocardial infarction, cerebrovascular accident (stroke), blindness (retinopathy)s, kidney disease, and lower limb amputations. Insulin and the oral antidiabetic drugs, along with diet and exercise, are the cornerstones of treatment for diabetes mellitus. They are used to prevent episodes of hypoglycemia and to normalize carbohydrate metabolism. There are two major types of diabetes mellitus: Type 1—Insulin-dependent diabetes mellitus (IDDM). Former names of this type of diabetes mellitus include juvenile diabetes, juvenile-onset diabetes, and brittle diabetes Type 2—Noninsulin-dependent diabetes mellitus (NIDDM). Former names of this type of diabetes mellitus include maturity-onset diabetes, adultonset diabetes, and stable diabetes. (A third one recently recorded – Gestational Diabetes) Those with type 1 diabetes mellitus produce insulin in insufficient amounts and therefore must have insulin supplementation to survive. Type 1 diabetes usually has a rapid onset, occurs before the age of 20 years, produces more severe symptoms than type 2 diabetes, and is more difficult to control. Major symptoms of type 1diabetes include hyperglycemia, polydipsia (increased thirst), polyphagia (increased appetite), polyuria (increased urination), and weight loss. Treatment of type 1 diabetes is particularly difficult to control because of the lack of insulin production by the pancreas. Treatment requires a strict regimen that typically includes a carefully calculated diet, planned physical activity, home glucose testing several times a day, and multiple daily insulin injections. Type 2 diabetes mellitus affects about 90% to 95% of individuals with diabetes. Those with type 2 diabetes mellitus either have a decreased production of insulin by the beta cells of the pancreas or a decreased

sensitivityof the cells to insulin, making the cells insulin resistant. Although type 2 diabetes mellitus may occur at any age, the disorder occurs most often after the age of 40 years. The onset of type 2 diabetes is usually insidious, symptoms are less severe than in type 1 diabetes mellitus, and because it tends to be more stable, it is easier to control than type 1 diabetes ORAL HYPOGLYCAEMIC AGENTS (ORAL ANTIDIABETIC DRUGS) The oral antidiabetic drugs are of value only in the treatment of patients with type 2 (NIDDM) diabetes mellitus whose condition cannot be controlled by diet alone. These drugs may also be used with insulin in the management of some patients with diabetes mellitus. Use of an oral antidiabetic drug with insulin may decrease the insulin dosage in some individuals. Two oral antidiabetic drugs (eg, a sulfonylurea and metformin) may also be used together when one antidiabetic drug and diet do not control blood glucose levels in type 2 diabetes mellitus.
I. Sulfonylureas . a) First generation: Acetohexamide , Chlorpropamide,

Tolazamide, Tolbutamide b) Second generation: Glyburide(Glibenclamide), Glipizide , Glimeperide, gliclazide
II. Meglitinides:

Repaglinide ,Nateglinide

III. Biguanides: Metformin , phenformin IV. Alpha- Glucosidase inhibitors: Acarbose, Miglitol V. Thiazolidinediones : Pioglitazone , Rosiglitazone

Sulfonylureas These agents Lower blood glucose by stimulating the beta cells of the pancreas to release insulin. The sulfonylureas are not effective if the beta cells of the pancreas are unable to release a sufficient amount of insulin to meet the individual’s needs. The first generation sulfonylureas (eg, chlorpropamide, tolazamide, and tolbutamide) are not commonly used today because they have a long duration of action and a higher incidence of adverse reactions, and are more likely to react with other drugs. More commonly used sulfonylureas are the second generation drugs, such as glimepiride , glipizide , and glyburide Biguanides Acts by reducing hepatic glucose production and increasing insulin sensitivity in muscle and fat cells. The liver normally releases glucose by detecting the level of circulating insulin. When insulin levels are high, glucose is available in the blood, and the liver produces little or no glucose. When insulin levels are low, there is little circulating glucose, so the liver produces more glucose. In type 2 diabetes, the liver may not detect levels of glucose in the blood and, instead of regulating glucose production, releases glucose despite blood sugar levels. Metformin sensitizes the liver to circulating insulin levels and reduces hepatic glucose production Alpha -Glucosidase Inhibitors: The alpha -glucosidase inhibitors, lower blood sugar by delaying the digestion of carbohydrates and absorption of carbohydrates in the intestine The α-glucosidase inhibitors primarily act to decrease postprandial hyperglycemia by slowing the rate at which carbohydrates are absorbed from the gastrointestinal tract. They act by competitively inhibiting α-glucosidases, a group of enzymes in the intestinal brush border epithelial cells that includes glycoamylase, sucrase, maltase, and dextranase. The prolongation of the intestinal absorption of carbohydrates results in a blunted insulin response, keeping postprandial hyperglycemia under control. To be effective, alpha glucosidase inhibitors must be taken before or with meals. Meglitinides: Like the sulfonylureas, the meglitinides act to lower blood glucose levels by stimulating the release of insulin from the pancreas. This action is dependent on the ability of the beta cell in the pancreas to produce some insulin. However, the action of the meglitinides is more rapid than that of the sulfonylureas and their duration of action much shorter. Because of this they must be taken three times a day.

Though structurally unrelated to sulfonylureas, the meglitinide class of hypoglycemic drugs bind to the same KATP channel as do the sulfonylureas, but it is unclear whether they bind to the same SUR1 subunit within the KATP complex. As a class, the meglitinides are incapable of stimulating insulin secretion in nutrient starved –beta cells, but in the presence of glucose, they demonstrate hypoglycemic effects by augmenting the release of insulin. Consequently, meglitinides seem relatively unlikely to cause fasting hypoglycemia. Thiazolidinediones: The thiazolidinediones, also called glitazones, decrease insulin resistance and increase insulin sensitivity by modifying several processes, with the end result being decreasing hepatic glucogenesis (formation of glucose from glycogen) and increasing insulindependent muscle glucose uptake. Thiazolidinediones activate the nuclear peroxisome proliferator–activated receptor (PPAR) , a nuclear orphan receptor that is predominantly expressed in adipose tissue and to a lesser extent in muscle, liver, and other tissues. The endogenous ligand for the PPAR- receptor is postulated to be prostaglandin J2, and it appears to work by heterodimerizing with other nuclear receptors to modulate the expression of insulinsensitive genes.

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